An enhanced state of in vivo carbonyl compound production by non-enzymatic biochemical reactions is called “carbonyl stress”. Carbonyl compounds are considered to be involved in aging and adult diseases, such as diabetes mellitus, and arteriosclerosis, via the Maillard reaction. The Maillard reaction is a non-enzymatic glycation reaction between a reducing sugar, such as glucose, and amino acids or proteins. Maillard reported this reaction in 1912, focusing on a phenomenon of brown coloration arising upon heating a mixture consisting of amino acid and reducing sugar (Maillard, L. C., Compt. Rend. Soc. Biol., 72:599 (1912)). The Maillard reaction is involved in brown coloration, generation of aromatic components, taste and protein denaturation, and such, during heating or storage of foods. Therefore, this reaction has been mainly studied in the field of food chemistry.
However, in 1968, glycated hemoglobin (HbAlc), a micro fraction of hemoglobin, was identified in vivo, and was further demonstrated to increase in patients with diabetes (Rahbar. S., Clin. Chim. Acta, 22: 296 (1968)). These findings brought attention to the significance of in vivo Maillard reactions, and the relationship between the reaction, the onset of adult diseases, such as diabetic complications and arteriosclerosis, and the progress of aging. For example, pyrraline and pentosidine, the late-stage products formed at post-Amadori compound formation reaction stages (advanced glycation end products; hereinafter abbreviated as AGE), are considered to serve as indices of aging and diabetes mellitus. In fact, highly reactive carbonyl compounds and AGE are accumulated at very high levels in blood and tissues of chronic renal failure patients, regardless of the presence or absence of hyperglycemia (Miyata, T. et al., Kidney Int., 51:1170–1181, 1997; Miyata, T. et al., J. Am. Soc. Nephrol., 7:1198–1206, 1996; Miyata, T. et al., Kidney Int. 55:389–399, 1999; Miyata, T. et al., J. Am. Soc. Nephrol. 9:2349–2356, 1998). This accumulation is ascribed to carbonyl stress in renal failure, which modifies proteins as a result of Maillard reaction with carbonyl compounds derived from sugars and lipids with amino groups (Miyata, T. et al., Kidney Int. 55:389–399, (1999)).
Thus, improving the carbonyl stress state by removing carbonyl compounds, which are generated in vivo, can result in the suppression of AGE formation associated with renal failure and thereby reduce tissue damages.
In peritoneal dialysis, waste products are excreted from blood across the peritoneum to the peritoneal dialysate. A peritoneal dialysate with high osmotic pressure (containing glucose, icodextrin, amino acids, and so on) delivers highly reactive carbonyl compounds accumulated in blood of renal failure patients across the peritoneum into the peritoneal dialysate in peritoneal cavity. This results in an increase in carbonyl compound concentration within the peritoneal dialysate to cause a carbonyl stress state. As a result, the peritoneal function is lowered, due to the modification of intraperitoneal proteins with carbonyl; this reaction, in turn, is presumed to be involved in the impairment of water-removing ability and ingravescence of peritoneal sclerosis (Miyata, T. et al., Kidney Int., 58:425–435, 2000; Inagi R., et al., FEBS Lett., 463:260–264, 1999; Ueda, Y., et al., Kidney Int. (in press); Combet, S., et al., J. Am. Soc. Nephrol., 11:717–728, 2000).
Indeed, the intraperitoneal carbonyl stress state induced by the introduction of glucose in peritoneal dialysis patients was demonstrated by immunohistochemical examination of the endothelia and mesothelia (Yamada, K. et al., Clin. Nephrol., 42: 354–361,1994; Nakayama, M. et al., Kidney Int., 51: 182–186,1997; Miyata, T. et al., Kidney Int., 58:425–435, 2000; Inagi R., et al., FEBS Lett., 463:260–264, 1999; Combet, S., et al., J. Am. Soc. Nephrol., 11:717–728, 2000). Thus, the carbonyl stress is also presumed to cause morphorgical changes in the peritoneum accompanied by functional (water-removing ability) impairment in dialysis patients. Therefore, a method to decrease the stress is needed in the art.
As a method for decreasing carbonyl stress in peritoneal dialysis patients, the present inventor has filed a patent (PCT/JP99/04521) relating to the use of carbonyl compound-trapping agents, such as aminoguanidine.
Biguanide agents, which have been used as therapeutic agents for diabetes mellitus, antimicrobial drugs, and antimalarial drugs, are known as compounds with a guanidine backbone. The biguanide agents have a basal backbone shown in formula (1), and contain a highly reactive imino group (=NH). Thus, the biguanide agents are expected to have a carbonyl compound-removing activity, like those of aminoguanidine. However, it has been believed that biguanide agents lack the glycation-suppressing effect because of the difference in three-dimensional structure between the two compounds (“New chemical therapy for diabetes mellitus” pp 22–31, 3. Biguanide Agents; S Tanaka, Medical Core (1997)).
